Gastrointestinal disorders such as active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), nocturnal acid breakthrough, severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome represent a major health concern impacting millions of people globally. In fact, it is estimated that as many as 60 million Americans alone experience acid reflux at least once a month, while approximately 19 million Americans suffer from GERD.
In the past, the above-described (and other related) gastrointestinal disorders and their associated symptoms have been treated with H2 histamine antagonists and antacids. Unfortunately, many such available treatments are not very effective in ameliorating the disorders themselves or their symptoms; additionally, many produce adverse side effects including, among others, constipation, diarrhea, and thrombocytopenia. Moreover, H2 antagonists such as ranitidine and cimetidine are relatively costly modes of therapy generally requiring multiple daily doses to produce some control of acid secretion. In addition, tolerance to H2 antagonists increases with continued use thus prohibiting clinical utility in chronic dosing settings.
More recently, at least some of the above-described gastrointestinal disorders have been treated with proton pump inhibitors (also called PPIs). PPIs are believed to reduce gastric acid production by inhibiting H+, K+-ATPase of the parietal cell—the final common pathway for gastric acid secretion. One particular class of PPIs includes substituted benzimidazole compounds that contain a sulfinyl group bridging substituted benzimidazole and pyridine rings.
At neutral pH, these PPIs are chemically stable, lipid-soluble compounds that have little or no inhibitory activity. It is believed that the neutral PPIs reach parietal cells from the blood and diffuse into the secretory canaliculi where they become protonated and thereby trapped. The protonated agent is then believed to rearrange to form a sulfenic acid and a sulfenamide. The sulfenamide, in turn, is thought to interact covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H+, K+-ATPase. See, Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 907, 9th ed. (1996).
The Assignee of the instant application, The Curators of the University of Missouri, was a party of a joint research agreement with Santarus, Inc. at the time the invention was made.
Unfortunately, most commercially available PPIs are unstable at neutral or acidic pH and undergo decomposition in gastrointestinal fluid upon oral administration, thereby resulting in loss of therapeutic activity. To overcome this acid instability, such compounds are typically formulated for oral delivery as enteric coated solid dosage forms, for example enteric coated tablets; the enteric coating protects the drug from contact with acidic stomach secretions. An undesirable consequence of such enteric coating is that therapeutic onset time is significantly delayed by comparison with non-enteric coated dosage forms. Such prolonged time to therapeutic onset is particularly undesirable for patients in need of rapid relief from one or more of the above described disorders or symptoms.
For example, U.S. Pat. No. 4,786,505 to Lovgren et al. discloses that a pharmaceutical oral solid dosage form of omeprazole must be protected from contact with acidic gastric juice by an enteric coating to maintain its pharmaceutical activity. That patent describes an enteric coated omeprazole preparation containing an alkaline core comprising omeprazole, a subcoating over the core, and an enteric coating over the subcoating.
Patients with GERD are typically given a once-daily dose of enteric coated PPI, administered in the morning, to manage daytime meal-induced gastric acid secretion. However, normal gastric acid secretion follows a circadian rhythm, with gastric acid secretion being most pronounced in the evening and early night. This results in a surge of gastric acidity around 2:00 am, with acid secretion decreasing toward the later morning. See e.g. Moore, J. G., Englert E., Circadian rhythm of gastric acid secretion in man. Nature 1970; 226:1261-2 and Prewett, E. J., Smith, J. T., Nwokolo, C. U., et al., Twenty-four hour intragastric acidity and plasma gastrin concentration profiles in female and male subjects. Clin. Sci. (Lond) 1991; 80:619-24. Unfortunately, it is recognized that commercially available enteric coated proton pump inhibitors fail to adequately control nighttime gastric acid secretion and nighttime GERD symptoms in many patients, regardless of when administered. For example, according to Tutuian R, et al., “[n]octurnal acid breakthrough occurs on any dosing regimen of oral proton pump inhibitors.” Alimentary Pharmacology & Therapeutics 2002; 16(3): 473-477. Furthermore, according to Katz P O, et al., “[n]octurnal acid breakthrough is frequently seen on proton pump inhibitors twice daily and is often accompanied by oesophageal reflux. This has important implications for medical therapy in patients with severe gastro-esophageal reflux and Barrett's oesophagus.” Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Alimentary Pharmacology & Therapeutics 1999; 12(12): 1231-1234.
Moreover, prolonged nocturnal esophageal acid exposure has been shown to contribute to the development of erosive esophagitis. See, e.g. Orr, W. C., Allen, M. L., Robinson, M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage Am J Gastroenterol. 1994 April; 89(4):509-12 and Hatlebakk, J. G., Berstad, A. Endoscopic grading of reflux oesophagitis: what observations correlate with gastroesophogeal reflux? Scand. J. Gastroenterol. 1997; 32:760-5.
Clearly, therefore, an unmet medical need exists for new formulations of proton pump inhibitors that can treat nighttime acid breakthrough and/or nighttime heartburn and other acid related disorders.